100,000 Genomes & Genomics England Tim Hubbard Genomics England King’s College London, King’s Health Partners Wellcome Trust Sanger Institute Global Leaders in Genomic Medicine Washington 8-9th January 2014 UK Health System 101 • Four separate health services – NHS England – NHS Wales – NHS Scotland – Health & Social Care in Northern Ireland (HSC) • NHS (England) – ~1.4 million employees – ~£110 billion annual budget • Structure in England changed 1st April 2013 https://www.gov.uk/government/organisations/department-of-health Linking Health data to Research Clinical Data Healthcare Professional World Genotype Electronic Health Record Whole Genome Sequencing Phenotype Electronic Genomic Biology Health Data World Records Reference Genotype and genome sequence Phenotype ~3 gigabytes relationship capture EBI: repositories (petabytes of genome sequence data) Human sequence data Sanger: sequencing repositories (1000 genomes, uk10K) Steps in UK towards E-Health Research, Genomic Medicine • Health data to Research – 2006 Creation of OSCHR • Increase coordination between funders: MRC and NIHR – 2007 OSCHR E-health board • Enable research access to UK EHR data • Build capacity for research on EHR data • Genomics to Health – 2009 House of Lords report on Genomic Medicine – 2010 Creation of Human Genomic Strategy Group (HGSG) 2011: UK Life Sciences Strategy No10: http://www.number10.gov.uk/news/uk-life-sciences-get-government-cash-boost/ BIS/DH: http://www.dh.gov.uk/health/2011/12/nhs-adopting-innovation/ Linking Health data to Research Clinical Data Healthcare Professional World Electronic Health Record Clinical Practice Phenotype Research Electronic Genomic Biology Datalink Health Data World Records (CRPD) Reference Genotype and genome sequence Phenotype ~3 gigabytes relationship capture Farr EBI: repositories (petabytes of genome Institute sequence data) Human sequence data Sanger: sequencing repositories (1000 genomes, uk10K) 2012: Human Genome Strategy Group report UK Life Science Strategy Update; 100K Genomes DH: http://www.dh.gov.uk/health/2012/01/genomics/ BIS: http://www.gov.uk/office-for-life-sciences/ Genomics England http://www.genomicsengland.co.uk/ @genomicsengland Linking Health data to Research Clinical Data Healthcare Professional World Electronic Health Record Clinical Practice Phenotype Research Electronic Genomic Biology Datalink Health Data World Records (CRPD) Reference Genotype and genome sequence Phenotype ~3 gigabytes relationship capture Farr EBI: repositories (petabytes of genome Institute sequence data) Human sequence data Sanger: sequencing repositories (1000 genomes, uk10K) Genomics England- mission • 100,000 patients with rare inherited disease, common cancers and pathogens from the NHS in England • Whole Genome Sequencing • Generate improved health and wealth for UK • Legacy of infrastructure, human capacity and capability • Become World-leader in Healthcare application of Genomic Medicine • £100m funding over the next 5 years Scale compared to existing WGS • 1000 genomes and UK10K – low coverage genomes (~4x illumina) • Limited number of ‘clinical grade’ WGS – TCGA: ~700 – ICGC: ~700 – WGS 500: 500 Is now the moment to commit to WGS - scale - Data Type Large structural changes Balanced translocations Distant consanguinity Uniparental disomy Novel/known coding variants non Novel/known coding variants Targeted gene sequencing SNP arraya Array CGH Exome Whole Genome Rare inherited diseases • 7% of the population or about 5/10,000 people • 7000 rare disorders- disabling, shorten life, costly • Circa 85% have a single gene defect • Early knowledge may avoid disability • Testing for >700 disorders extant within the NHS diagnostic laboratory network (UKGTN) • Represents <1/4 of known disease genes. • Whole Genome Sequencing 25-50% increase in discovery Genomics England Will look for mutual wins • NIHR Translational Research Collaborative • NHS Clinical Genetics Service & Organ Based Specialists • WGS500 - Oxford • International Rare Diseases Consortium – Aiming for 200 new treatments • Deciphering Developmental Disorders (Exome) • Link to trial opportunities for new therapies • Increased recognition from industry of the value of niche markets Cancer • Lung Cancer -40 000 cases/year in the UK, (35K die/year) • Largest cause of cancer death, therapies modestly effective only applicable to 10-15% of patients • CRUK Stratified Medicine’s initiative • Other Cancers - Breast, colon, prostate and unknown primary • Rare and Childhood Cancers • Drugs target mutations • Tumour heterogeneity Incidence v survival at 5 years Pathogens • Stratifying response, minimising adverse events and tracking outbreaks • HIV –Treatment for life and resistance testing is in the care pathway. • Hepatitis C genotype selects therapy • M. Tuberculosis resistance and epidemiology Genomics England – Operational Plan Clinical Genetics, Cancer, Public Health, NHS Trusts, Patients & Public Rare diseases, common cancers and pathogens Broad consent, characteristics, genetic data capture and samples Primary Care Refreshable identifiable Hospital episodes DNA repository Mortality data Clinical Data Patient entry Life-course registry Linked to anonymised Annotation & QC Whole Genome Sequence Scientists & SMEs Sequencing Centres Product comparison Sequential builds of refreshed clinical grade Anonymised Clinical data and DNA sequence Safe haven- users work within Fire wall Patient data stays on NHS side Only processed results pass outside Training & Clinicians & Industry Academics capacity Genomics England – Implementation Plan • Phase 1: bake-offs – Sequencing comparison underway – Annotation comparison to follow • Phase 2: Pilots – 2000 Rare Inherited Disease WGS- 30x depth –January 2014 – 3000 Cancer Patients (Lung, Breast & Colon) – Each 1000 somatic (50x) and 1000 germline (30x) – tender imminent – Pathogens pilot will be planned with Public Health England • Phase 3: Main study – 30,000 WGS per year • Education – Developing a National Programme to transform capacity and capability – UK Universities and Medical Schools Process Overview Sample Sequence Variants Candidate Clinical Clinical DNA (BAM) (VCF) Variants Interpretation Action Process Overview Sample Sequence Variants Procured DNA (BAM) (VCF) Sequence Variants Candidate Clinical Procured (VCF) Variants Interpretation Annotation Clinical Sequence Interpretation Validation GeL Clinical Database NHS Action Sample Sequence Variants Procured DNA (BAM) (VCF) Sequence Sequence Variants Procured (BAM) (VCF) Refinement Variants Candidate Clinical Procured (VCF) Variants Interpretation Annotation Clinical Sequence Interpretation Validation GeL Clinical Database NHS Action Sequencing assessment • Bake off in progress – samples with suppliers • Evaluation will be on quality and coverage Annotation assessment • Harder than assessing sequencing • Gold standard less well defined • Lack of established data standards Past assessment exercises • CASP – Critical Assessment of Structure Prediction (since 1994, CASP11 in 2014) • GASP, RGASP – Gene prediction and RNAseq assessments • CLARITY Challenge – 2012 – http://genes.childrenshospital.org/ • CAGI – 2010, 2011, 2013 – https://genomeinterpretation.org/ Data provided by GeL • Sequence from providers (BAM+VCF) – Rare diseases: trio – Cancer: germline + tumour • Phenotype data available to clinicians Types of annotation anticipated • Filtered, ranked lists of variants with estimates of pathogenicity and confidence • Expected impact at level of genes, pathway • Tools organising literature around affected genes, pathways • Clear, simple clinical reports • Suggested clinical interventions Assessment criteria • Accuracy • Clinically informative • Rapid turnaround • Understandable output • Standardised output data formats • Ability to operate at scale – 2014: ~25 samples/day (pilot) – 2015: ~50 samples/day – 2017: ~100 samples/day Initial annotation assessment • Information collection exercise on 15 samples – Investigate levels of annotation available • Minimal file format requirements – Will inform future specifications for file formats • Will select multiple suppliers for pilot – Ability to deliver timely, consistent data, etc. Ongoing assessment during Phase 2 • Precise file format requirements, with optional sections • Best suppliers will be invited to tender to provide annotation for main programme (2015-2017) Annotation expectations for Phase 3 • Software will run as Virtual Machines within GeL datacentre, c.f. Apps • Software will be subject to evolving compliance requirements, c.f. CLIA dry lab • No need for ‘Apps’ to be comprehensive: potential for specialist software, e.g. specific diseases, pharmacogenomics etc. Genomics England • 100,000 WGS on NHS patients and pathogens • Aware of the challenges • Working with NHS, academics and industry to drive Genomic Medicine into the NHS • Support that with education • Leave a legacy of NGS Centres, sample pipeline and biorepository, large-scale data store that makes this usable by the NHS • New diagnostics and therapies and opportunities for patients • By end of 2017 Acknowledgements Genomics England NHS England Genome Strategy Board Department of Health Human Genome Strategy Group Wellcome Trust Sanger Institute Discussions with many at Wellcome Trust, OSCHR, NIH, ENCODE .